ABSTRACT

It has been reported that prior exposure of thyroid tissue to TSH in vitro induces a state of refractoriness to new challenges of the hormone. We have investigated the effect of repeated TSH treatment on thyroid secretion to determine whether such refractoriness exists in vivo. The rate of thyroid secretion was estimated by measuring the rate of hydrolysis of labelled thyroglobulin from mouse thyroid glands in vitro. The thyroid glands were labelled in vivo with ¹³¹I and then cultured for 20 h in the presence of mononitrotyrosine, an inhibitor of iodotyrosine deiodinase. The rate of hydrolysis of labelled thyroglobulin was measured as the percentage of radioactivity released as free iodotyrosines and iodothyronines into the gland and the medium at the end of incubation. Thyrotrophin was administered in vivo at hourly intervals for 2–4 injections. The corresponding control group received saline injections every hour except for the last injection when they received TSH. The peak rates of thyroglobulin hydrolysis, measured 2 h following the last injection, were similar in animals receiving two, three or four TSH injections and were not different from those in the control groups. Serum tri-iodothyronine and thyroxine concentrations 2 h after the last injection were higher in the groups receiving multiple TSH injections. Thyroidal cyclic AMP accumulation in response to TSH was markedly depressed in the group receiving multiple injections compared with the group receiving a single injection of TSH in vivo. These data indicate that (1) the stimulatory effect of TSH on thyroidal secretion is not diminished by prior administration of the hormone in vivo, (2) repeated TSH administrations in vivo cause refractoriness of the adenylate cyclase response to TSH and (3) a dichotomy exists between the secretory response and the adenylate cyclase response to repeated administrations of TSH.

J. Endocr. (1985) 106, 153–157

The rates of thyroglobulin hydrolysis and iodothyronine release from mouse thyroid glands were studied in vitro. Recently iodinated thyroglobulin ('new pool') had been labelled during life by injection of ¹³¹I 3 h before removal of the thyroid, 'old pool' thyroglobulin had been labelled by the administration of ¹²⁵I in the drinking water for 1 week starting 3 weeks earlier. Chromatographic analysis of pronase digests of the thyroid glands showed that the iodothyronine content of the old and new pools were 19·5 and 7·4 per cent respectively. In the basal state the rate of thyroglobulin hydrolysis was lower from the old pool but the rate of hormone secretion was similar from both pools. Thyrotrophin (TSH) increased the rate of thyroglobulin hydrolysis and hormone release from both pools by up to four to six times the basal rate, the effect being maximal 2 h after administration of TSH and lasting for 6–8 h. The rate of thyroglobulin hydrolysis after TSH was similar in both pools but the rate of release of labelled iodothyronines was significantly higher from the old pool. These studies have indicated that although hydrolysis of thyroglobulin proceeds faster in the new pool than in the old ('last come, first served' hypothesis) nevertheless there is no difference in the rate of hormone secretion from the two pools, and hydrolysis in both pools is affected by TSH.

ABSTRACT

Several studies have shown that iodine plays a role in spontaneous autoimmune thyroiditis in man and other animals. In addition, abnormalities of iodine metabolism have been found in patients with Hashimoto's thyroiditis and in chickens of the obese strain (OS), an animal model of spontaneous autoimmune thyroiditis. We have examined several parameters of iodine metabolism before immune damage in this model and in the related Cornell strain (CS), a strain which develops a late-onset mild thyroiditis, to discover a possible causal relationship between altered iodine metabolism and the initiation of autoimmunity.

Thyroglobulin was purified from individual chicken thyroid glands and analysed for iodine by the ceric sulphate method. Analogous to the thyroglobulin of Hashimoto's patients, the iodine content of OS thyroglobulin (27 atoms/molecule) was lower than that of normal-strain thyroglobulin (46 atoms/molecule) when the chickens were provided with a normal diet. Also, under conditions of TSH suppression, the iodine content of OS thyroglobulin (18 atoms/molecule) was lower than that of CS thyroglobulin (36 atoms/molecule) and of normal-strain thyroglobulin (32 atoms/molecule). In contrast with Hashimoto's patients, however, the OS and CS chickens had practically no inorganic iodide in their thyroid glands; electrophoretic analysis of thyroid homogenates revealed that essentially all (> 99·62%) ¹²⁵I was organified by 16 h in all strains of birds tested. Despite the relatively poor iodination of thyroglobulin exhibited by OS chickens, they did not iodinate additional 'unique' proteins, when examined by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) of thyroid proteins labelled with ¹²⁵I in vivo.

The release of ¹²⁵I in vivo under conditions of TSH suppression was examined in chicks receiving thyroxine and propylthiouracil. After 14 days both OS and CS chicks showed poorly suppressible release of 85% and 92% respectively, while the normal strain released 33 %. To determine whether the autonomous function of OS and CS thyroid glands was present in a restricted number of follicles or cells or whether it occurred in a majority of cells, autoradiograms of thyroid glands labelled in vivo from TSH-suppressed chickens were examined. Silver grains were present in all cells, indicating that autonomous function was a characteristic of all cells.

These thyroid gland abnormalities are compared with those found in Hashimoto's patients and discussed in the context of their aetiological significance.

Journal of Endocrinology (1991) 128, 239–244